JP2023551441A - Glycoside derivatives and their production methods and applications - Google Patents

Abstract

The present invention provides glycoside derivatives and their production methods and applications. Specifically, the present invention provides a glycoside derivative which is a compound represented by the following formula I or a pharmaceutically acceptable salt thereof. The glycoside derivatives according to the invention can be used for the treatment of type II diabetes or type I diabetes. JPEG2023551441000082.jpg4278

Description

Cross-reference This application claims priority to Chinese Patent Application No. 202011302722.4, filed with the State Intellectual Property Administration of China on November 19, 2020, with the title of invention "Glycoside derivatives and their manufacturing method and applications" , the contents of which are incorporated herein by reference in their entirety.

The present invention relates to the technical field of chemicals, and in particular to glycoside derivatives and their manufacturing methods and applications.

Currently, there are approximately 110 million diabetic patients in China out of more than 400 million diabetic patients worldwide, so the market value of diabetes treatment drugs is high. Diabetes is a chronic comprehensive disease whose main symptoms are disorders of glucose metabolism caused by absolute or relative insulin deficiency and decreased sensitivity of target cells to insulin. The development of is a result of the joint action of peripheral insulin resistance and defective β-cell function.

The design concept of this application is derived from Chinese herbal medicine mango leaves. Mango leaves are used folkly to lower blood sugar levels. Modern pharmacological research shows that the active ingredient in mango leaves for lowering blood sugar levels is the natural product mangiferin. The compound of the present application was obtained through two series of structural optimizations using mangiferin as a lead compound.

According to the literature, mangiferin exerts a direct hypoglycemic effect by increasing the regenerative capacity of insulin cells, insulin levels, insulin sensitivity, glucose utilization rate, etc., and that mangiferin exerts a direct hypoglycemic effect by increasing the regenerative capacity of insulin cells, insulin levels, insulin sensitivity, glucose utilization rate, etc., and that mangiferin can be injected intraperitoneally to reduce oxidative damage. Mangiferin can significantly reduce the amount of glycated hemoglobin in diabetic rats, that mangiferin has a certain therapeutic effect on diabetic nephropathy, and that mangiferin can significantly reduce the amount of glycated hemoglobin in diabetic rats. It has been reported that it may delay the disease.

However, mangiferin has the disadvantages of low water solubility of the compound, low oral bioavailability, and relatively mild hypoglycemic effects. Therefore, the inventors aimed to improve the pharmacokinetic properties of mangiferin and increase its bioavailability, thereby enhancing its medicinal efficacy in lowering blood sugar levels and reducing the risk of diabetic complications, as well as reducing toxic side effects on the human body. The structure of mangiferin was optimized with the aim of reducing the

Since the chemical structure of mangiferin is similar to that of an SGLT-2 inhibitor compound, which is a hypoglycemic drug, the chemical structure of mangiferin was optimized to target SGLT-2. Screening for SGLT-2 target inhibitory activity in vitro discovered a series of compounds with good hypoglycemic activity, and further in vivo animal experimental studies showed that this series was effective in type 1 and type 2 diabetic animal models. Confirmed that it works for both. And there is a statistically significant advantage compared to dapagliflozin.

The SGLT-2 inhibitor class of hypoglycemic drugs has the advantage of cardiovascular benefits compared to other hypoglycemic drugs. However, the SGLT-2 inhibitor compounds in the prior art are still unsatisfactory in terms of biological activity, duration of efficacy, safety, etc.

The present invention has been made in view of the above circumstances, and aims to provide an SGLT-2 inhibitor compound that has high therapeutic efficacy, high safety, long duration of drug efficacy, and requires less frequency of administration to patients. purpose.

In order to solve the above technical problem, the present invention provides a glycoside derivative which is a compound represented by the following formula I or a pharmaceutically acceptable salt thereof.

In the formula, A is an oxygen atom, -(CH ₂ ) _m - or -NH-, m is 1, 2 or 3,
B is an oxygen atom or a sulfur atom,
R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ are independently hydrogen, hydroxy group, carboxy group, halogen, -CN, alkyl group, alkoxy group, alkoxyalkoxy group, cycloalkyl group, aryl group, heteroaryl group, -O-aryl group, -O-heteroaryl group, -OCH ₂ -aryl group, -OCH ₂ -heteroaryl group, -O-heterocyclyl group, -OCH ₂ -heterocyclyl group, ester group, -NR ₁₁ R _11a and a 3- to 14-membered heterocyclyl group containing 1 to 4 heteroatoms selected from N, O, S, SO and/or SO ₂ ,
Alternatively, said R ₁ and R ₂ are taken together to form a heterocyclyl group, cycloalkyl group, aryl group or heteroaryl group fused to a benzene ring, and/or said R ₃ and R ₄ are taken together , forming a cyclopentyl group or oxacyclopentyl group fused to a benzene ring,
R ₇ , R ₈ , R ₉ , R ₁₀ are independently selected from the group consisting of hydrogen, hydroxy group, alkyl group, alkoxy group and alkylthio group,
R ₁₁ and R _11a are independently selected from the group consisting of a hydrogen atom and an alkyl group,
Here, the alkyl group, alkoxy group, alkoxyalkoxy group, cycloalkyl group, aryl group, heteroaryl group, -O-aryl group, -O-heteroaryl group, -OCH ₂ -aryl group, -OCH ₂ -hetero Aryl group, -O-heterocyclyl group, -OCH ₂ -heterocyclyl group, ester group, -NR ₁₁ R _11a , heterocyclyl group, alkylthio group are halogen, hydroxy group, amino group, carboxy group, cyano group, alkyl group, alkoxy It may be further substituted with one or more substituents selected from the group consisting of nitro groups and nitro groups.

More preferably, the alkyl group, alkoxy group, alkoxyalkoxy group, cycloalkyl group, aryl group, heteroaryl group, -O-aryl group, -O-heteroaryl group, -OCH ₂ -aryl group, -OCH ₂ - Heteroaryl group, -O-heterocyclyl group, -OCH ₂ -heterocyclyl group, ester group, -NR ₁₁ R _11a , heterocyclyl group, alkylthio group are halogen, hydroxy group, amino group, carboxy group, cyano group, C1 to C6 It may be further substituted with one or more substituents selected from the group consisting of an alkyl group, a C1-C6 alkoxy group, and a nitro group.

In the present invention, preferably the above A is an oxygen atom or -CH ₂ -.

In the present invention, preferably B is an oxygen atom.

In the present invention, preferably, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ are independently hydrogen, hydroxy group, carboxy group, halogen, -CN, C1-C6 alkyl group, C1- C6 alkoxy group, C2 to C16 alkoxyalkoxy group, C3 to C6 cycloalkyl group, C6 to C12 aryl group, C2 to C12 heteroaryl group, -O-C6 to C12 aryl group, -O-C2 to C12 heteroaryl group, -OCH ₂ -C6 to C12 aryl group, -OCH ₂ -C2 to C12 heteroaryl group, -O-C2 to C6 heterocyclyl group, -OCH ₂ -C2 to C6 heterocyclyl group, C1 to C6 ester group, -NR ₁₁ R _11a and 3- to 14-membered heterocyclyl groups containing 1 to 4 heteroatoms selected from N, O, S, SO and/or SO ₂ .

Here, R ₁₁ and R _11a are independently selected from the group consisting of a hydrogen atom and an alkyl group, and more preferably a hydrogen atom or a C1 to C6 alkyl group. In some specific embodiments of the present invention, R ₁₁ and R _11a are independently H, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t- selected from the group consisting of butyl, n-pentyl, isopentyl, n-hexyl and isohexyl.

More preferably, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are independently hydrogen, hydroxy group, carboxy group, fluorine, chlorine, bromine, -CN, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, isopentyl group, n-hexyl group, isohexyl group, methoxy group, ethoxy group, n-propyloxy group, isopropyl Oxy group, n-butyloxy group, isobutyloxy group, t-butyloxy group, n-pentyloxy group, isopentyloxy group, n-hexyloxy group, methoxymethoxy group, ethoxymethoxy group, ethoxyethoxy group, n-propoxymethoxy group group, isopropoxymethoxy group, n-propoxyethoxy group, isopropoxyethoxy group, cyclopropyl group, methylcyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, phenyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyrrolyl group , thienyl group, furanyl group, oxazolyl group, thiazolyl group, imidazolyl group, triazolyl group, phenoxy group, pyridyloxy group, pyrimidinyloxy group, pyrrolyloxy group, furanyloxy group, thienyloxy group, oxazolyloxy group, benzyloxy group, -OCH ₂ -pyridyl group, -OCH ₂ -pyrimidinyl group, -OCH ₂ -pyrrolyl group, -OCH ₂ -thienyl group, -OCH ₂ -furanyl group, -OCH ₂ -oxazolyl group, -OCH ₂ -thiazolyl group, - OCH ₂ -imidazolyl group, -OCH ₂ -triazolyl group, methyl ester group, ethyl ester group, isopropyl ester group, sulfonic acid ester group, amino group, hexahydropyridyl group, hexahydropyrazinyl group, morpholinyl group, tetrahydro selected from the group consisting of pyrrolyl group and tetrahydroxazolyl group.

In the present invention, one or more hydrogen atoms in the above group are selected from the group consisting of halogen, hydroxy group, amino group, carboxy group, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group and nitro group. It may be further substituted with one or more substituents.

More preferably, the substituents include fluorine, chlorine, bromine, hydroxy group, amino group, carboxy group, cyano group, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, isopropoxy and nitro group.

In some specific embodiments of the invention, the phenoxy group specifically includes:

etc.

In some specific embodiments of the invention, the -O-C2-C12 heteroaryl group specifically includes:

etc.

In some specific embodiments of the invention, the -OCH ₂ -C6-C12 aryl group is specifically PhCH ₂ O-,

etc.

In some specific embodiments of the invention, the -OCH ₂ -C2-C12 heteroaryl group specifically includes:

etc.

In some specific embodiments of the invention, the C6-C12 aryl group is specifically a phenyl group, p-methylphenyl group, p-fluorophenyl group, o-chlorophenyl group, m-methoxyphenyl group. base, or

etc.

In some specific embodiments of the invention, the C2-C12 heteroaryl group specifically includes:

etc.

In some specific embodiments of the invention, the C1-C6 alkyl group is specifically -CF ₃ , CHF ₂ , CH ₂ F, and the like.

In some specific embodiments of the invention, the C1-C6 alkoxy group is specifically -OCHF ₂ , -OCF ₃ and the like.

In some specific embodiments of the present invention, the C2-C16 alkoxyalkoxy group is specifically a methoxymethoxy group, an ethoxymethoxy group, an ethoxyethoxy group, an n-propoxymethoxy group, an isopropoxymethoxy group, These include n-propoxyethoxy group, isopropoxyethoxy group, and the like.

In some specific embodiments of the invention, the -O-C2-C6 heterocyclyl group specifically includes:

etc.

In some specific embodiments of the invention, the C1-C6 ester group specifically includes:

etc.

In some specific embodiments of the present invention, the -NR ₁₁ R _11a above specifically represents an amino group,

etc.

In some specific embodiments of the invention, the 3- to 14-membered heterocyclyl group containing 1 to 4 heteroatoms selected from N, O, S, SO, and/or _SO2 is Specifically,

etc.

In some specific embodiments of the invention, said R ₁ and R ₂ are together selected from 1-4 selected from N, O, S, SO and/or SO ₂ fused to a benzene ring. forms a 3- to 14-membered heterocyclyl group, a C3-C6 cycloalkyl group, a C6-C12 aryl group, or a C2-C12 heteroaryl group containing 5 heteroatoms.

In the present invention, preferably, R ₁ and R ₂ are taken together to form a cyclohexyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyrrolyl group, a thienyl group, a furanyl group, an oxazolyl group, Forms a thiazolyl group, imidazolyl group, triazolyl group, hexahydropyridyl group, hexahydropyrazinyl group, morpholinyl group, tetrahydropyrrolyl group, tetrahydroxazolyl group or dioxane.

The dioxane is preferably 1,4-dioxane, ie a dioxane group.

Preferably in the present invention, R ₇ , R ₈ , R ₉ and R ₁₀ are independently selected from the group consisting of hydrogen, hydroxy group, C1-C6 alkyl group, C1-C6 alkoxy group and C1-C6 alkylthio group. Ru.

More preferably, R ₇ , R ₈ , R ₉ , and R ₁₀ are independently hydrogen, hydroxy group, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t- Butyl group, n-pentyl group, isopentyl group, n-hexyl group, isohexyl group, hydroxymethyl group, hydroxyethyl group, methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, n-butyloxy group, isobutyloxy group, t-butyloxy group, n-pentyloxy group, isopentyloxy group, n-hexyloxy group, methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, isobutylthio group, t- selected from the group consisting of butylthio group, n-pentylthio group, isopentylthio group and n-hexylthio group.

In some specific embodiments of the invention, the glycoside derivative is a compound represented by Formula Ia below or a pharmaceutically acceptable salt thereof:

In the formula, the definitions of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₁₀ are the same as above, and their explanations are omitted here.

Preferably R ₁₀ is a hydroxymethyl group or a methylthio group.

In some specific embodiments of the invention, the glycoside derivative is a compound represented by Formula II below or a pharmaceutically acceptable salt thereof.

In the formula, A is an oxygen atom, -(CH ₂ ) _m - or -NH-, m is 1, 2 or 3,
B is an oxygen atom or a sulfur atom,
R ₃ , R ₄ , R ₅ , and R ₆ are independently hydrogen, hydroxy group, carboxy group, halogen, -CN, alkyl group, alkoxy group, alkoxyalkoxy group, cycloalkyl group, aryl group, heteroaryl group, -O-aryl group, -O-heteroaryl group, -OCH ₂ -aryl group, -OCH ₂ -heteroaryl group, -O-heterocyclyl group, -OCH ₂ -heterocyclyl group, ester group, -NR ₁₁ R _11a , and 3- to 14-membered heterocyclyl groups containing 1 to 4 heteroatoms selected from N, O, S, SO and/or _SO2 ,
_R10 is selected from the group consisting of hydrogen, hydroxy group, alkyl group, alkoxy group and alkylthio group,
R ₁₁ and R _11a are independently selected from the group consisting of a hydrogen atom and an alkyl group,
Here, the alkyl group, alkoxy group, alkoxyalkoxy group, cycloalkyl group, aryl group, heteroaryl group, -O-aryl group, -O-heteroaryl group, -OCH ₂ -aryl group, -OCH ₂ -hetero Aryl group, -O-heterocyclyl group, -OCH ₂ -heterocyclyl group, ester group, -NR ₁₁ R _11a , heterocyclyl group, alkylthio group are halogen, hydroxy group, amino group, carboxy group, cyano group, alkyl group, alkoxy It may be further substituted with one or more substituents selected from the group consisting of nitro groups and nitro groups.

More preferably, the alkyl group, alkoxy group, alkoxyalkoxy group, cycloalkyl group, aryl group, heteroaryl group, -O-aryl group, -O-heteroaryl group, -OCH ₂ -aryl group, -OCH ₂ - Heteroaryl group, -O-heterocyclyl group, -OCH ₂ -heterocyclyl group, ester group, -NR ₁₁ R _11a , heterocyclyl group, alkylthio group are halogen, hydroxy group, amino group, carboxy group, cyano group, C1 to C6 It may be further substituted with one or more substituents selected from the group consisting of an alkyl group, a C1-C6 alkoxy group, and a nitro group.

In the present invention, preferably the above A is an oxygen atom or -CH ₂ -.

In the present invention, preferably B is an oxygen atom.

In the present invention, preferably, R ₃ , R ₄ , R ₅ , and R ₆ are independently hydrogen, hydroxy group, carboxy group, halogen, -CN, C1-C6 alkyl group, C1-C6 alkoxy group, C2- C16 alkoxyalkoxy group, C3-C6 cycloalkyl group, C6-C12 aryl group, C2-C12 heteroaryl group, -O-C6-C12 aryl group, -O-C2-C12 heteroaryl group, -OCH ₂ -C6- C12 aryl group, -OCH ₂ -C2 to C12 heteroaryl group, -O-C2 to C6 heterocyclyl group, -OCH ₂ -C2 to C6 heterocyclyl group, C1 to C6 ester group or -NR ₁₁ R _11a and N, O, It is selected from the group consisting of 3- to 14-membered heterocyclyl groups containing 1 to 4 heteroatoms selected from S, SO and/or SO ₂ .

Here, R ₁₁ and R _11a are independently selected from the group consisting of a hydrogen atom and an alkyl group, and more preferably a hydrogen atom or a C1 to C6 alkyl group. In some specific embodiments of the present invention, R ₁₁ and R _11a are independently H, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t- It is selected from a butyl group, an n-pentyl group, an isopentyl group, an n-hexyl group, an isohexyl group, and the like.

More preferably, R ₃ , R ₄ , R ₅ , and R ₆ are independently hydrogen, hydroxy group, carboxy group, halogen, -CN, C1-C6 alkyl group, C1-C6 alkoxy group, and C2-C16 selected from the group consisting of alkoxyalkoxy groups;

More preferably, said R ₃ is selected from the group consisting of a C1-C3 alkyl group and a C1-C3 alkoxy group,
R ₄ , R ₅ and R ₆ are hydrogen.

The C1-C3 alkyl group and C1-C3 alkoxy group are further substituted with one or more substituents selected from the group consisting of halogen, hydroxy group, amino group, carboxy group, cyano group, and nitro group. Good too.

More preferably, R ₃ , R ₄ , R ₅ and R ₆ are independently hydrogen, hydroxy group, carboxy group, fluorine, chlorine, bromine, -CN, methyl group, ethyl group, n-propyl group, Isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, isopentyl group, n-hexyl group, isohexyl group, methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, n- Butyloxy group, isobutyloxy group, t-butyloxy group, n-pentyloxy group, isopentyloxy group, n-hexyloxy group, methoxymethoxy group, ethoxymethoxy group, ethoxyethoxy group, n-propoxymethoxy group, isopropoxymethoxy group group, n-propoxyethoxy group, isopropoxyethoxy group, cyclopropyl group, methylcyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, phenyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyrrolyl group, thienyl group, furanyl group group, oxazolyl group, thiazolyl group, imidazolyl group, triazolyl group, phenoxy group, pyridyloxy group, pyrimidinyloxy group, pyrrolyloxy group, furanyloxy group, thienyloxy group, oxazolyloxy group, benzyloxy group, -OCH ₂ -pyridyl group, -OCH ₂ -pyrimidinyl group, -OCH ₂ -pyrrolyl group, -OCH _{2 -thienyl group, -OCH 2 -furanyl group, -OCH 2 -oxazolyl} group, -OCH ₂ -thiazolyl group, -OCH ₂ -imidazolyl group , -OCH ₂ -triazolyl group, methyl ester group, ethyl ester group, isopropyl ester group, sulfonic acid ester group, amino group, hexahydropyridyl group, hexahydropyrazinyl group, morpholinyl group, tetrahydropyrrolyl group and tetrahydro selected from the group consisting of oxazolyl groups.

In the present invention, one or more hydrogen atoms in the above group are selected from the group consisting of halogen, hydroxy group, amino group, carboxy group, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group and nitro group. It may be further substituted with one or more substituents.

More preferably, the substituents include fluorine, chlorine, bromine, hydroxy group, amino group, carboxy group, cyano group, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, isopropoxy and nitro group.

In some embodiments of the invention,
A is -(CH ₂ )- or an oxygen atom,
B is an oxygen atom,
R ₁ and R ₂ together form a 5- to 6-membered heterocyclyl group fused to a benzene ring, or a cyclobutanyl group fused to a benzene ring, and the 5- to 6-membered heterocyclyl group is a 5- to 6-membered heterocyclyl group containing 1 or 2 heteroatoms selected from O and S,
R ₃ is selected from the group consisting of CH ₃ (CH ₂ ) _n -, CH ₃ (CH ₂ ) _n O- and halogen, n is selected from 0, 1, 2 and 3;
R ₄ is hydrogen;
Alternatively, R ₃ and R ₄ together form a cyclopentyl group or an oxacyclopentyl group fused to a benzene ring,
R ₅ and R ₆ are hydrogen;
R ₇ , R ₈ and R ₉ are hydroxy groups,
R ₁₀ is selected from the group consisting of hydroxyalkyl, alkoxy and alkylthio groups.

In other embodiments of the invention,
A is -(CH ₂ )- or an oxygen atom,
B is an oxygen atom,
R ₁ and R ₂ together form a 5- to 6-membered heterocyclyl group fused to a benzene ring, or a cyclobutanyl group fused to a benzene ring, and the 5- to 6-membered heterocyclyl group is A 5- to 6-membered heterocyclyl group containing 1 or 2 oxygen atoms,
R ₃ is selected from the group consisting of CH ₃ (CH ₂ ) _n -, CH ₃ (CH ₂ ) _n O- and halogen, n is selected from 0, 1, 2 and 3;
R ₄ is hydrogen;
Alternatively, R ₃ and R ₄ together form a cyclopentyl group or an oxacyclopentyl group fused to a benzene ring,
R ₅ and R ₆ are hydrogen;
R ₇ , R ₈ and R ₉ are hydroxy groups,
R ₁₀ is selected from the group consisting of hydroxymethyl, methoxy and methylthio.

In some embodiments of the invention,
A is an oxygen atom,
B is an oxygen atom,
R ₁ is selected from the group consisting of C1-C3 alkoxy groups,
R ₂ is hydrogen;
R ₃ is selected from halogen, preferably fluorine, chlorine or bromine;
R ₄ is hydrogen;
R ₅ and R ₆ are hydrogen;
R ₇ , R ₈ and R ₉ are hydroxy groups,
R ₁₀ is selected from hydroxyalkyl groups, preferably hydroxymethyl groups.

In some specific embodiments of the invention, the phenoxy group specifically includes:

etc.

In some specific embodiments of the invention, the -O-C2-C12 heteroaryl group specifically includes:

etc.

In some specific embodiments of the invention, the -OCH ₂ -C6-C12 aryl group is specifically PhCH ₂ O-,

etc.

In some specific embodiments of the invention, the -OCH ₂ -C2-C12 heteroaryl group specifically includes:

etc.

In some specific embodiments of the invention, the C6-C12 aryl group is specifically a phenyl group, p-methylphenyl group, p-fluorophenyl group, o-chlorophenyl group, m-methoxyphenyl group. base, or

etc.

In some specific embodiments of the invention, the C2-C12 heteroaryl group specifically includes:

etc.

In some specific embodiments of the invention, the C1-C6 alkyl group is specifically -CF ₃ , CHF ₂ , CH ₂ F, and the like.

In some specific embodiments of the invention, the C1-C6 alkoxy group is specifically -OCHF ₂ , -OCF ₃ and the like.

In some specific embodiments of the present invention, the C2-C16 alkoxyalkoxy group is specifically a methoxymethoxy group, an ethoxymethoxy group, an ethoxyethoxy group, an n-propoxymethoxy group, an isopropoxymethoxy group, These include n-propoxyethoxy group, isopropoxyethoxy group, and the like.

In some specific embodiments of the invention, the -O-C2-C6 heterocyclyl group specifically includes:

etc.

In some specific embodiments of the invention, the C1-C6 ester group specifically includes:

etc.

In some specific embodiments of the present invention, the -NR ₁₁ R _11a above specifically represents an amino group,

etc.

In some specific embodiments of the invention, the 3- to 14-membered heterocyclyl group containing 1 to 4 heteroatoms selected from N, O, S, SO and/or _SO2 is specifically Specifically,

etc.

Preferably in the present invention, R ₁₀ is selected from the group consisting of hydrogen, hydroxy group, C1-C6 alkyl group, C1-C6 alkoxy group and C1-C6 alkylthio group.

More preferably, R ₁₀ is selected from the group consisting of hydrogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy and C1-C3 alkylthio.

The C1-C3 alkyl group, C1-C3 alkoxy group, or C1-C3 alkylthio group has one or more substituents selected from the group consisting of halogen, hydroxy group, amino group, carboxy group, cyano group, and nitro group. may be further replaced by

More preferably, R ₁₀ is hydrogen, hydroxy group, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, isopentyl group, n -Hexyl group, isohexyl group, hydroxymethyl group, hydroxyethyl group, methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, n-butyloxy group, isobutyloxy group, t-butyloxy group, n-pentyloxy group , isopentyloxy group, n-hexyloxy group, methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, isobutylthio group, t-butylthio group, n-pentylthio group, isopentylthio group , and n-hexylthio group.

In some specific embodiments of the invention, the glycosidic derivative is a compound having any of the following structures, or a pharmaceutically acceptable salt thereof:

In some specific embodiments of the invention, the glycosidic derivative is a compound having any of the following structures, or a pharmaceutically acceptable salt thereof:

In some specific embodiments of the invention, the glycoside derivative is a compound having the following structure or a pharmaceutically acceptable salt thereof:

A second object of the present invention is a method for producing the above-mentioned glycoside derivatives, which comprises producing a compound represented by the following formula I-a from a compound represented by the following formula III through a deprotection reaction. The goal is to provide the following.

In the formula, the definitions of A, B, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are the same as above, and their explanations are omitted here.

R ₁₀ is a hydroxymethyl group.

R ₁₂ is an alkyl group (an example of an alkyl group is a C1 to C6 alkyl group, such as a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group) , n-pentyl group, isopentyl group, n-hexyl group, or isohexyl group), TMS- (trimethylsilyl group), Bn- (benzyl group), formyl group, Ac- (acetyl group), THP - (tetrahydropyranyl group), MOM- (methoxymethyl group), or TBDMS- (t-butyldimethylsilyl group).

When R ₁₂ is TMS- or TBDMS-, the deprotecting reagent is, by way of example, TBAF. For example, when R ₁₂ is Bn-, the deprotection reaction conditions are H ₂ /Pd-C, H ₂ /Pt-C, or H ₂ /Pd(OH) ₂ -C. For example, when R ₁₂ is Ac-, the conditions for the deprotection reaction are strong base conditions (eg, aqueous sodium hydroxide or potassium hydroxide) or strong acid conditions. For example, when R ₁₂ is THP- or MOM-, the deprotection reaction conditions are acidic conditions (e.g., aqueous hydrochloric acid, hydrogen chloride in ethyl acetate (HCl(g)/EtOAc), hydrogen chloride in methanol (HCl (g)/CH ₃ OH), a hydrogen chloride ethanol solution (HCl(g)/EtOH), or a hydrogen chloride dioxane solution (HCl(g)/dioxane)). As an example, when R ₁₂ is a methyl group or the like, the deprotecting reagent is concentrated hydrochloric acid, hydrobromic acid, concentrated sulfuric acid or boron tribromide.

In the above production method, in a preferred embodiment, the compound represented by the formula III is produced from the compound represented by the formula IV.

Here, the definitions of A, B, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₁₂ are the same as above, and the description thereof will be omitted here.

Illustratively, reaction conditions for preparing a compound of formula III from a compound of formula IV include BF ₃ . It is _Et2O .

In a preferred embodiment of the above production method, the compound represented by the formula IV is produced by reacting the compound represented by the formula V with the compound represented by the formula VI.

Here, the definitions of A, B, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₁₂ are the same as above, and the description thereof will be omitted here.

R ₁₃ is -H, -F, -Cl, -Br, -I, -OMs, -OTs, -OTf.

The reaction reagent for producing the compound represented by formula IV from the compound represented by formula V and the compound represented by formula VI is, for example, LDA (lithium diisopropylamide) or n-BuLi (N-butyl lithium), etc.

In some specific embodiments of the invention, the reaction pathway of the glycosidic derivatives is as follows:

In some specific embodiments of the invention, the reaction pathway of the glycosidic derivatives is as follows:

The present invention provides another method for producing the above-mentioned glycoside derivatives, in which a compound represented by the following formula I-a is produced from a compound represented by the following formula VII through a sulfurization reaction and a deprotection reaction. Provided is a manufacturing method including:

Here, the definitions of A, B, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ are the same as above, and the description thereof will be omitted here.

R ₁₀ is a methylthio group.

Preferably B is an O atom.

R ₁₂ is an alkyl group (an example of an alkyl group is a C1 to C6 alkyl group, such as a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group) , n-pentyl group, isopentyl group, n-hexyl group, or isohexyl group), TMS- (trimethylsilyl group), Bn- (benzyl group), formyl group, Ac- (acetyl group), THP - (tetrahydropyranyl group), MOM- (methoxymethyl group), or TBDMS- (t-butyldimethylsilyl group).

Illustratively, the sulfurizing reagent in the sulfurizing reaction is thiourea.

Illustratively, when R ₁₂ is TMS- or TBDMS-, the deprotecting reagent is TBAF. When R ₁₂ is Bn-, the conditions for the deprotection reaction include, for example, H ₂ /Pd-C, H ₂ /Pt-C, or H ₂ /Pd(OH) ₂ -C. When R ₁₂ is Ac-, the conditions for the deprotection reaction are, for example, strong base conditions (eg, aqueous sodium hydroxide solution, aqueous potassium hydroxide solution, etc.) or strong acid conditions. When R ₁₂ is THP- or MOM-, the deprotection reaction conditions are, for example, acidic conditions (e.g., aqueous hydrochloric acid solution, hydrogen chloride ethyl acetate solution (HCl(g)/EtOAc), hydrogen chloride methanol solution (HCl( g)/CH ₃ OH), hydrogen chloride in ethanol (HCl(g)/EtOH), or hydrogen chloride in dioxane (HCl(g)/dioxane)). When R ₁₂ is a methyl group or the like, the deprotecting reagent is, by way of example, concentrated hydrochloric acid, hydrobromic acid, concentrated sulfuric acid or boron tribromide.

In a preferred embodiment of the above production method, the compound represented by Formula VII is produced from the compound represented by Formula VIII.

Here, the definitions of A, B, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ are the same as above, and the description thereof will be omitted here.

Illustratively, reaction conditions for producing a compound of formula VII from a compound of formula VIII are _AC2O , DMAP, TEA.

In a preferred embodiment of the above manufacturing method, the compound represented by the formula VIII is manufactured from the compound represented by the following formula IX.

Here, the definitions of A, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ are the same as above, and their explanations are omitted here.

Illustratively, the conditions for preparing the compound of formula VIII from the compound of formula IX are AcOH, _H2O .

In the above production method, in a preferred embodiment, the compound represented by the formula IX is produced by reacting a compound represented by the following formula V with a compound represented by the following formula X, and then performing a reduction reaction. be done.

Here, the definitions of A, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ are the same as above, and their explanations are omitted here.

R ₁₃ is -H, -F, -Cl, -Br, -I, -OMs, -OTs, -OTf.

Illustratively, the catalyst used for the reaction of the compound of formula V and the compound of formula X is t-BuMgCl.

Illustratively, the conditions for the reduction reaction are CeCl ₃ and NaBH ₄ .

In some specific embodiments of the invention, the reaction pathway of the glycosidic derivatives is as follows:

A third object of the present invention is to provide an intermediate compound or a salt thereof having the structure represented by the following formula IV:

In the formula, the definitions of A, B, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₁₂ are the same as above, and their explanations are omitted here.

The present invention also provides another intermediate compound having a structure represented by the following formula IX or a salt thereof:

In the formula, the definitions of A, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ are the same as above, and their explanations are omitted here.

In some specific embodiments of the invention, the intermediate has any of the following structures:

A fourth object of the present invention is to combine the above glycoside derivative or the glycoside derivative produced by the above production method with a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, medium, or a combination thereof. An object of the present invention is to provide a pharmaceutical composition comprising the following.

In the present invention, the types of carriers, excipients, diluents, auxiliaries, and vehicles are not particularly limited, and, for example, applicable carriers, excipients, diluents, auxiliaries, and vehicles well known to those skilled in the art may be used. can be mentioned.

A fifth object of the present invention is to use the above-mentioned glycoside derivatives, the glycoside derivatives produced by the above-mentioned production method, or the above-mentioned pharmaceutical compositions in the production of pharmaceuticals for preventing, treating or alleviating diabetes and its complications. It is to provide applications.

In the present invention, the diabetes can be selected from type I diabetes and type II diabetes, and is preferably type II diabetes.

The complication is preferably a cardiovascular disease due to type II diabetes.

The above glycoside derivative provided by the present invention, the glycoside derivative produced by the above production method, or the above pharmaceutical composition improves blood sugar control or protects cardiovascular disease in adult patients with type II diabetes. It can be used to quickly and safely lower blood sugar without causing the risk of hypoglycemia.

In the present invention, the above-mentioned glycoside derivatives can be used in combination with other drugs for preventing, treating, or alleviating diabetes and its complications.

A sixth object of the present invention is to prevent diabetes and its complications by contacting a biological sample or a patient with the above glycoside derivative, the glycoside derivative produced by the above production method, or the above pharmaceutical composition. , to provide a method for treatment or mitigation. In one specific aspect, the method for preventing, treating or alleviating diabetes and its complications comprises using the glycoside derivative according to the present invention, the glycoside derivative produced by the above production method, or the above pharmaceutical composition. , including applying it to patients who need it.

In comparison to the prior art, the present invention provides glycosidic derivatives having the structure represented by formula I or pharmaceutically acceptable salts thereof.

Compared with the prior art, the present invention has the following technical effects.
1. The present invention provides novel glycoside derivatives that have therapeutic effects on type II diabetes. Compared with the prior art, the glycoside derivatives according to the present invention have excellent therapeutic effects on type II diabetes when used in high, medium, and low doses.

2. The method for producing glycoside derivatives according to the present invention uses inexpensive and easily available chemical products as starting materials, and the synthesis yield in each step is high, so the production cost is low and it is more suitable for industrial production.

term:
Unless otherwise stated, terms used in this application, including the specification and claims, are defined as follows. It should be noted that in the specification and the appended claims, nouns that are not modified by numbers may generally refer to a plurality, unless otherwise specified. Unless otherwise specified, methods commonly used in biochemistry and pharmacology, such as mass spectrometry, nuclear magnetism, and HPLC, are used.

The term "alkyl group" as used herein is intended to encompass branched and straight chain saturated aliphatic hydrocarbon groups having the given number of carbon atoms. For example, "C1-C6 alkyl group" means an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include methyl group (Me), ethyl group (Et), propyl group (e.g. n-propyl group and isopropyl group), butyl group (e.g. n-butyl group, isobutyl group, t-butyl group). ) and pentyl groups (eg, n-pentyl group, isopentyl group, neopentyl group), but are not limited thereto. Preferred alkyl groups are C1-C6 alkyl groups, and more preferred alkyl groups are C1-C4 alkyl groups.

The term "alkoxy group" or "alkyloxy group" refers to the group -O-alkyl. "C1-C6 alkoxy group" (or alkyloxy group) is intended to include C1, C2, C3, C4, C5 and C6 alkoxy groups. Preferred alkoxy groups are C1-C6 alkoxy groups, and more preferred alkoxy groups are C1-C4 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy), and t-butoxy. Similarly, "alkylthio group" or "thioalkoxy group" represents an alkyl group as defined above having the specified number of carbon atoms, linked via a bridging sulfur, for example methyl-S- or ethyl-S- It is.

The term "carbonyl group" refers to an organic functional group (C=O) in which two atoms, carbon and oxygen, are bonded by a double bond.

The term "aryl group" refers to a monocyclic, bicyclic or tricyclic ring system having a total of 5 to 12 ring members, in which at least one ring is an aromatic ring. and each ring in the cyclic system contains 3 to 7 ring atoms. Monocyclic aryl refers to a phenyl group. Bicyclic and bicyclic or more aryl refer to naphthyl group, anthracenyl group, etc. Further, this aryl bicyclic ring may be one in which a cycloalkyl group, a cycloalkenyl group, or a cycloalkynyl group is condensed to a benzene ring. Preferably, the aryl group is a C6-C12 aryl group. In certain embodiments of the invention, "aryl" refers to aromatic ring systems including, but not limited to, phenyl, biphenyl, indenyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthyl. Point. The term "aralkyl group" or "arylalkyl group" refers to the residue of an alkyl group attached to an aryl ring, non-limiting examples include benzyl group, phenethyl group, and the like. A fused aryl group can be attached to another group at a suitable position on the cycloalkyl or aromatic ring. For example, an arrow line drawn from a ring system represents a bond connectable to any suitable ring atom.

The term "cycloalkyl group" refers to a monocyclic or bicyclic cyclic alkyl group. Monocyclic cyclic alkyl groups refer to C3-C8 cyclic alkyl groups including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl groups. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl groups are included in the definition of "cycloalkyl group." Bicyclic cyclic alkyl groups include bridged rings, spiro rings or fused cyclic cycloalkyl groups. Preferably, the cycloalkyl group is a C3-C6 cycloalkyl group.

"Halo" or "halogen" includes fluorine, chlorine, bromine and iodine. "Haloalkyl group" is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and substituted with one or more halogens. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl and Examples include, but are not limited to, heptachloropropyl groups. Examples of haloalkyl groups include "fluoroalkyl groups" which are intended to include branched and straight chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms and substituted with one or more fluorine atoms. Can be mentioned.

"Haloalkoxy group" or "haloalkyloxy group" means a haloalkyl group as defined above having the specified number of carbon atoms attached through a bridging oxygen. For example, "C1-C6 haloalkoxy group" is intended to include C1, C2, C3, C4, C5 and C6 haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy groups. Similarly, a "haloalkylthio group" or a "thiohaloalkoxy group" represents a haloalkyl group as defined above having the specified number of carbon atoms attached through a bridging sulfur, such as trifluoromethyl-S- and Mention may be made of pentafluoroethyl-S-.

The term "heteroaryl group" refers to a stable 3-, 4-, 5-, 6-, or 7-membered aromatic monocyclic ring or aromatic bicyclic ring, or a 7-, 8-, 9-, means a 10-, 11-, 12-, 13-, or 14-membered aromatic polycyclic heterocycle that is completely unsaturated, partially unsaturated, and composed of carbon atoms, N, O, and S. 1, 2, 3 or 4 independently selected heteroatoms. Examples of the "heteroaryl group" include any of the following polycyclic groups, in which any of the above-defined heterocycles in these polycyclic groups is fused to a benzene ring, and a nitrogen and sulfur heterocyclic group is fused to a benzene ring. Atoms may optionally be oxidized. The nitrogen atom can be substituted or unsubstituted (ie, N or NR, where R is H or another substituent as defined). The heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclyl groups described herein may be substituted on a carbon or nitrogen atom so long as the resulting compound is stable. The nitrogen in the heterocycle may optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle does not exceed 1. Preferred heteroaryl groups are 5- to 12-membered heteroaryl groups. Examples of heteroaryl groups include acridinyl group, azetidinyl group, azocine group, benzimidazolyl group, benzofuranyl group, benzothiofuranyl group, benzothienyl group, benzoxazolyl group, benzoxazolinyl group, benzothiazolyl group. group, benzotriazolyl group, benzotetrazolyl group, benzisoxazolyl group, benzisothiazolyl group, benzimidazolinyl group, carbazolyl group, 4aH-carbazolyl group, carbonyl group, chromanyl group, Chromenyl group, cinnolinyl group, decahydroquinolinyl group, 2H,6H-1,5,2-dithiazinyl group, dihydrofuro[2,3-b]tetrahydrofuranyl group, furanyl group, furazanyl group, imidazolidinyl group, imidazolinyl group, imidazolyl group, 1H-indazolyl group, imidazopyridyl group, indolenyl group, dihydroindolyl group, indolizinyl group, indolyl group, 3H-indolyl group, isatinoyl group, isobenzofuranyl group, isochromanyl group, isoindazolyl group , isodihydroindolyl group, isoindolyl group, isoquinolinyl group, isothiazolyl group, isothiazolopyridyl group, isoxazolyl group, isoxazolopyridyl group, methylenedioxyphenyl group, morpholinyl group, diazanaphthyl group, octahydroquinolinyl group, oxadiazolyl group , 1,2,3-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,2,5-oxadiazolyl group, 1,3,4-oxadiazolyl group, oxazolidinyl group, oxazolyl group, oxazolopyridyl group, oxazolidinyl group , perimidinyl group, oxiindolyl group, pyrimidinyl group, phenanthridinyl group, phenanthrolinyl group, phenazinyl group, phenothiazinyl group, phenoxathiyl group, phenoxazinyl group, phthalazinyl group, piperazinyl group, piperidine group, piperidinonyl group , 4-piperidinonyl group, piperonyl group, pteridinyl group, purinyl group, pyranyl group, pyrazinyl group, pyrazolidinyl group, pyrazolinyl group, pyrazolopyridyl group, pyrazolyl group, pyridazinyl group, pyridoxazolyl group, pyridimidazolyl group, pyridothiazolyl group, pyridyl group, Pyrimidinyl group, pyrrolidinyl group, pyrrolinyl group, 2-pyrrolidonyl group, 2H-pyrrolyl group, pyrrolyl group, quinazolinyl group, quinolinyl group, 4H-quinazinyl group, quinoxalinyl group, quinuclidinyl group, tetrazolyl group, tetrahydrofuranyl group, tetrahydroisoquinol group Nyl group, tetrahydroquinolinyl group, 6H-1,2,5-thiadiazinyl group, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,5-thiadiazolyl group, 1,3 , 4-thiadiazolyl group, thianthrenyl group, thiazolyl group, thienyl group, thiazolopyridyl group, thienothiazolyl group, thienoxazolyl group, thienimidazolyl group, thienyl group, triazinyl group, 1,2,3-triazolyl group, 1, 2,4-triazolyl group, 1,2,5-triazolyl group, 1,3,4-triazolyl group and xanthenyl group, quinolinyl group, isoquinolinyl group, phthalazinyl group, quinazolinyl group, indolyl group, isoindolyl group, isodihydroindolyl group group, 1H-indazolyl group, benzimidazolyl group, 1,2,3,4-tetrahydroquinolinyl group, 1,2,3,4-tetrahydroisoquinolinyl group, 5,6,7,8-tetrahydro- Examples include, but are not limited to, quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl. In the present invention, the heteroaryl group is preferably a C2-C12 heteroaryl group or a C5-C12 heteroaryl group.

The term "heterocyclyl group" or "heterocycloalkyl group" as used herein refers to a monocyclic heterocycloalkyl system or a bicyclic heterocycloalkyl system. A monocyclic heterocycloalkyl group refers to a 3- to 8-membered saturated or unsaturated but non-aromatic cyclic alkyl system containing at least one selected from O, N, S, P. A preferred heterocycloalkyl group is a 3- to 12-membered heterocyclyl group or a 3- to 6-membered heterocyclyl group, and a preferred heterocyclyl group is an -O-C2-C6 heterocyclyl group.

The term "substitution" as used herein means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that normal valences are maintained and said substitution results in a stable compound. .

When any variable appears more than once in any composition or formula of a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, where a group is indicated to be substituted with 0, 1, 2 or 3 R groups, said group may optionally be substituted with up to 3 R groups, and At each occurrence R is independently selected from those defined as R. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term "patient" as used herein refers to the organism being treated by the methods of the invention. Such organisms preferably include, but are not limited to, mammals (eg, mice, monkeys/monkeys, horses, cows, pigs, dogs, cats, etc.), and most preferably refer to humans.

As used herein, the term "effective amount" refers to, for example, a drug or agent that elicits a biological or medical response in a tissue, system, animal, or human that is sought by a researcher or clinician (i.e., means the amount of compound related to Additionally, the term "therapeutically effective amount" means that the amount ameliorates, treats, cures, prevents, or alleviates a disease, disease, or side effect, or improves the disease or disease or side effect as compared to a corresponding subject not receiving the amount described above. It means the amount that can reduce the speed of disease progression. An effective amount may be given in one or more administrations, applications or doses and is not intended to be limited by particular formulation or route of administration. The term also encompasses effective amounts within its range that are capable of enhancing normal physiological function.

As used herein, the term "treatment" includes bringing about any effect such as amelioration of a disease, disorder, disability, such as alleviation, reduction, modulation, amelioration or elimination, or of the symptoms thereof. It's an improvement. As used herein, administration of certain compounds or pharmaceutical compositions can ameliorate a disease, symptom or condition, and in particular ameliorate its severity, delay its onset, or slow its progression. It may be possible to delay or shorten the duration of the condition. This can be due to circumstances related to medication, whether fixed or episodic, continuous or intermittent. The term "prevention" as used herein means to prevent, interrupt, or eliminate the development of a disease or condition before it occurs, or to prevent or slow the progression of a disease.

The term "pharmaceutical composition" as used herein refers to a composition that is a combination of an active agent and an inert or active carrier, particularly for in vivo or ex vivo diagnostic or therapeutic applications.

The term "medicinal" or "pharmaceutically acceptable" as used herein means that, within the scope of reasonable medical judgment, there is no possibility of undue toxicity, irritation, allergic reactions and/or other problems or complications. Used to refer to compounds, substances, compositions and/or dosage forms that are suitable for use in contact with human and animal tissue, without associated with a reasonable benefit/risk ratio.

As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically possible carrier" refers to liquid or solid fillers, diluents, excipients, manufacturing aids (e.g., lubricants, talc, , magnesium stearate, calcium stearate or zinc stearate or stearic acid) or a solvent encapsulated substance, which is used for transport from one organ or body part to another. Concerning the delivery or transport of active compounds. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient.

In order to further explain the present invention, the glycoside derivatives provided by the present invention, their manufacturing methods, and applications will be described in detail below with reference to Examples.

Preparation of Examples:
Example 1 Preparation of compound 1

(1) Under stirring conditions, 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid (2.30 g, 12.806 mmol, 1.3 equivalents) and 5-bromo-2-methoxyphenol (2 Cu(AcO) ₂ (1.97 g, 10.836 mmol, 1.1 eq.) and pyridine (2.34 g, 29.0 g, 29.0 g, 9.851 mmol, 1.00 eq.) in dichloromethane (50.00 mL) were added. 552 mmol, 3 eq.) was added and the resulting mixture was stirred at room temperature under an atmosphere of air for 48 hours. 100 mL of _H2O was added to the above mixture. The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic phases were washed with saturated brine (1 x 100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (5:1) to give 6-(5-bromo-2-methoxyphenoxy)-2,3-dihydro-1,4-benzodioxane (1134 mg). , yield 34.14%) as an off-white solid.

The reaction route is as follows:

(2) 6-(5-bromo-2-methoxyphenoxy)-2,3-dihydro-1,4-benzodioxane (100.00 mg, 0.297 mmol, 1.00 equivalent) under nitrogen protection and stirring conditions. n-BuLi (0.24 mL, 0.594 mmol, 2.00 equivalents) was added dropwise to a solution of 1.0 in tetrahydrofuran (1.00 mL) at a dropping temperature of -78°C. The resulting mixture was stirred at -78°C under nitrogen atmosphere for 1 hour. Add (3R,4S,5R,6R)-3,4,5-tri(benzyloxy)-6-[(benzyloxy)methyl]oxan-2-one (479.26 mg, 0.890 mmol), 3. 00 equivalents) in tetrahydrofuran (1.00 mL) was added dropwise at a dropping temperature of -78°C. The resulting mixture was stirred for an additional hour at -78°C. The reaction was warmed to room temperature, the reaction was quenched at room temperature with saturated NH ₄ Cl (aq.), and the resulting mixture was extracted with EA (2×3 mL). The combined organic phases were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated by distillation under reduced pressure. The crude product was used directly in the next step without further purification.

The reaction route is as follows:

(3) Under nitrogen protection and stirring conditions, (3R,4S,5R,6R)-3,4,5-tri(benzyloxy)-6-[(benzyloxy)methyl]-2-[3-(2 ,3-dihydro-1,4-benzodioxin-6-oxyl)-4-methoxyphenyl]oxan-2-ol (540.00 mg, 1.00 eq.) and TES (157 mg) in acetonitrile (4 ml). BF ₃ -Et ₂ O was added dropwise at a dropping temperature of -30°C, and the reaction was allowed to proceed for 30 minutes. The reaction was monitored by LCMS. After the reaction was completed, the reaction was quenched with K ₂ CO ₃ (aq) for 1 h at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography on a C18 silica gel column, mobile phase acetonitrile-water, gradient 40% to 85%, elution time 10 minutes and detector UV 254 nm. 6-[2-methoxy-5-[(2R,3S,4R,5R,6R)-3,4,5-tri(benzyloxy)-6-[(benzyloxy)methyl]oxan-2-yl]phenoxy ]-2,3-dihydro-1,4-benzodioxane (470 mg, yield 85.9%) was obtained as an off-white solid.

The reaction route is as follows:

(4) 6-[2-methoxy-5-[(2R,3S,4R,5R,6R)-3,4,5-tri(benzyloxy)-6-[(benzyloxy)methyl]oxy-2- [yl]phenoxy]-2,3-dihydro-1,4-benzodioxane (500.00 mg, 1.00 equivalent) and 15% Pd/C were stirred in a methanol solution at 50° C. under hydrogen atmosphere overnight. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography on a C18 silica gel column, mobile phase acetonitrile-water, gradient 10% to 50%, elution time 30 minutes, detector UV 254 nm. (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-1,4-benzodioxin-6-oxyl)-4-methoxyphenyl]-6-(hydroxymethyl)oxane- 3,4,5-triol (140 mg, yield 52.0%) was obtained as an off-white solid.

The reaction equation is as follows:

LC-MS: (ES, m/z): [M-1] =419;
¹ H NMR: (400 MHz, Methanol-d ₄ ) δ 7.22 (dd, J= 8.4, 2.1 Hz, 1H), 7.13 - 7.03 (m, 2H), 6.74 (d, J = 8.6 Hz, 1H), 6.44 - 6.36 (m, 2H), 4.24 - 4.16 (m, 4H), 4.07 (d, J = 9.4 Hz, 1H), 3.88 (dd, J = 12.0, 1.5 Hz, 1H), 3.80 (s, 3H), 3.76 - 3.65 (m, 1H), 3.51 - 3.32 (m, 5H).

Example 2 Preparation of Compound 2 (1) 6-bromo-2,3-dihydro-1,4-benzodioxane (4.40 g, 1.00 eq) and Mg (2.00 g, 5 .00 equivalent) solution was stirred at 50° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. 5-Bromo-2-methylbenzaldehyde (3.00 g, 1.00 equivalents) was added dropwise to the above mixture, and the reaction system temperature was maintained at 0° C., and the addition was completed within 10 minutes. The resulting mixture was stirred for an additional 2 hours at room temperature. The reaction was monitored by LCMS. After the reaction was completed, the reaction was quenched with an ice water mixture at 0°C. The resulting mixture was extracted with EtOAc (3x30 mL). The combined organic phases were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography on a C18 silica gel column, mobile phase acetonitrile-water, gradient 20% to 70%, 5 min, detector UV 254 nm. (5-bromo-2-methylphenyl)(2,3-dihydro-1,4-benzodioxin-6-yl)methanol (4.8 g, 69.6% yield) was prepared as an off-white solid.

The reaction route is as follows:

(2) (5-bromo-2-methylphenyl)(2,3-dihydro-1,4-benzodioxin-6-yl)methanol (4.80 g, 1.00 eq.) and TES (3.4 g, 2 0 equivalent) was added to acetonitrile (80 mL) to form a mixture, and BF ₃ -Et ₂ O was added dropwise to the above mixture under nitrogen atmosphere and stirring conditions at a dropping temperature of -30°C. The resulting mixture was stirred at −30° C. for 1 hour under nitrogen atmosphere. The reaction was monitored by LCMS. After the reaction was completed, the reaction was quenched with K ₂ CO ₃ at −20° C. The resulting mixture was extracted with EtOAc (3 x 70 mL). The combined organic phases were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography on a C18 silica gel column, mobile phase MeOH-water, gradient 20% to 60%, 25 min, detector UV 254 nm. 6-[(5-bromo-2-methylphenyl)methyl]-2,3-dihydro-1,4-benzodioxane (3.6 g, 78.0% yield) was prepared as an off-white solid.

The reaction route is as follows:

(3) 6-[(5-bromo-2-methylphenyl)methyl]-2,3-dihydro-1,4-benzodioxane (3.60 g, 1.20 eq.) under stirring and nitrogen protection conditions. n-BuLi (1.2 eq) was added dropwise to the tetrahydrofuran mixture at a dropping temperature of -78°C.

(3aS,5S,6S,6aS)-2,2-dimethyl-5-(morpholine-4-carbonyl)-tetrahydrofuran[2,3-d][1,3]dioxole under nitrogen protected conditions with stirring. To a mixture of -6-ol (2.50 g, 1.00 eq) in tetrahydrofuran (15 mL) was added t-BuMgCl (6.1 mL) dropwise over 30 minutes at a dropwise temperature of 0°C.

The solutions obtained above were mixed and reacted with stirring at -78°C for 30 minutes. The reaction was monitored by LCMS. After the reaction was completed, NH ₄ Cl (aq.) (5 mL) was added at room temperature to quench the reaction. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography on a C18 silica gel column, mobile phase acetonitrile-water, gradient 15% to 60%, elution time 20 minutes, detector UV254. (3aR,5S,6R,6aR)-5-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-methylbenzoyl]-2,2-dimethyl-tetrahydrofuran[2, 3-d][1,3]dioxin-6-ol (4.6 g, 95.0% yield) was prepared as an off-white solid.

The reaction route is as follows:

(4) Under nitrogen protection and stirring conditions, (3aR,5S,6R,6aR)-5-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-methylbenzoyl] -2,2-dimethyl-tetrahydrofuran[2,3-d][1,3]dioxol-6-ol (4.60 g, 1.00 eq.) and CeCl _{3.7H 2} O (5.20 g, 1.30 eq. NaBH 4 (0.50 g, 1.20 equivalent) was added to a methanol (20 mL) solution of NaBH ₄ (0.50 g, 1.20 equivalent) and reacted at -30°C for 30 min. The reaction was monitored by LCMS. After the reaction was completed, HCl (2N) was added to quench the reaction at -30°C. The resulting mixture was extracted with EtOAc (3 x 40 mL). The combined organic phases were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography on a C18 silica gel column, mobile phase acetonitrile-water, gradient 10% to 50%, elution time 10 minutes, detector UV 254 nm. (3aR,5R,6S,6aR)-5-[[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-methylphenyl](hydroxy)methyl]-2,2- Dimethyl-tetrahydrofuran[2,3-d][1,3]dioxin-6-ol (2.6 g, 56.2% yield) was obtained as an off-white solid.

The reaction route is as follows:

(5) (3aR,5R,6S,6aR)-5-[[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-methylphenyl](hydroxy)methyl]-2 ,2-dimethyl-tetrahydrofuran[2,3-d][1,3]dioxol-6-ol (2.60 g, 1.00 eq.) and AcOH (20 mL) in H ₂ O (20 mL) at 100 °C. The reaction was stirred for 4 hours. The reaction was monitored by LCMS. After the reaction was completed, the reaction system was concentrated under reduced pressure, and the resulting concentrate was extracted with EtOAc (3 x 100 mL). The combined organic phases were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography on a C18 silica gel column, mobile phase acetonitrile-water, gradient 10% to 40%, elution time 15 minutes, detector UV 254 nm. (2S,3S,4R,5R)-6-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-methylphenyl]oxane-2,3,4,5-tetra All (2.25 g, 95.0% yield) was obtained as an off-white solid.

The reaction route is as follows:

(6) Under stirring conditions, (2S,3S,4R,5R)-6-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-methylphenyl]oxane-2 , 3,4,5-tetrol (2.25 g, 1.00 eq.) and Ac ₂ O (3.55 g) in acetonitrile (20 mL), TEA (3.52 g, 6.00 eq.) and DMAP ( 8.00 mg, 0.01 equivalent) was added thereto, and the reaction was stirred at room temperature for 1.5 h. The reaction was monitored by LCMS. After the reaction was completed, the resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography on a C18 silica gel column, mobile phase methanol-water, gradient 40% to 70%, elution time 10 minutes, detector UV 254 nm. 3,4,5-tri(acetoxy)-6-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-methylphenyl]oxan-2-yl acetate (2.08 g , purity 64.5%) was obtained as an off-white solid.

The reaction route is as follows:

(7) Under stirring conditions, 4,5-bis(acetoxy)-2-(carbamoylthio)-6-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4- CH ₃ I (1.20 g, 3.00 equivalents) was added thereto, and the mixture was reacted at room temperature for 24 hours. The reaction was monitored by LCMS. After the reaction was completed, the reaction was quenched with ice water mixture at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic phases were concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography on a C18 silica gel column, mobile phase acetonitrile-water, gradient 50% to 70%, elution time 20 minutes, detector UV 254 nm. 4,5-bis(acetoxy)-6-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-methylphenyl]-2-(methylthio)oxy-3-yl acetate (1.09 g, yield 71.8%) was obtained as an off-white solid.

The reaction route is as follows:

(8) Under stirring conditions, add 4,5-bis(acetoxy)-6-[3-(2,3-dihydro-1, 4-Benzodioxin-6-ylmethyl)-4-methylphenyl]-2-(methylthio)oxy-3-yl acetate (1.09 g, 2.00 mmol) was added and reacted for 1 hour at room temperature to saturate the mixture. Acidified to pH 2 with NaHSO ₄ (aq.). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic phases were concentrated by distillation under reduced pressure. The residue was purified by reverse phase flash chromatography on a C18 silica gel column, mobile phase acetonitrile-water, gradient 10% to 50%, elution time 15 minutes, detector UV 254 nm. 2-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-methylphenyl]-6-(methylthio)oxane-3,4,5-triol (520.1 mg, yield 44.6%) as an off-white solid.

The reaction route is as follows:

LC-MS: (ES, m/z):[M+23] =441.
¹ H NMR:(400 MHz, DMSO-d6) δ 7.09 (s, 3H), 6.77 - 6.70 (m, 1H), 6.62 - 6.56 (m, 2H), 5.19 (d, J = 5.5 Hz, 1H), 5.08 (d, J = 4.5 Hz, 1H), 4.84 (d, J = 5.5 Hz, 1H), 4.33 (d, J = 9.4 Hz, 1H), 4.05 (d, J = 9.1 Hz, 1H), 3.81 ( s, 2H), 3.32 (d, J = 1.8 Hz, 1H), 3.31 - 3.13 (m, 2H), 2.17 (s, 3H), 2.05 (d, J = 14.1 Hz, 3H).

Example 3 Preparation of Compound 3 (1) Under stirring conditions, 4-ethoxyphenylboronic acid (5.20 g, 31.329 mmol, 1.30 equivalents) and 5-bromo-2-chlorophenol (5.00 g, 24 Cu(AcO) ₂ (4.82 g, 26.512 mmol, 1.1 eq.) and pyridine (5.72 g, 72.307 mmol, 1.0 eq.) in dichloromethane (100 mL) were added. 1 equivalent) was added thereto, and the mixture was allowed to react at room temperature for 2 days. The reaction was quenched with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic phases were concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with PE to give 4-bromo-1-chloro-2-(4-ethoxyphenoxy)benzene (1.2 g, yield 15.20%) as an off-white solid. Ta.

The reaction equation is as follows:

(2) 4-bromo-1-chloro-2-(4-ethoxyphenoxy)benzene (900.00 mg, 2.747 mmol, 1.00 equivalent) in THF (15.00 mL) under nitrogen atmosphere and stirring conditions. n-BuLi (2.20 mL, 5.500 mmol, 2.00 equivalent) was added dropwise to the solution at a dropping temperature of -78°C. After 1 hour, (3R,4S,5R,6R)-3,4,5-tri(benzyloxy)-6-[(benzyloxy)methyl]oxan-2-one was added to the above mixture at -78°C. (3.70 g, 6.868 mmol, 2.50 eq.) in THF (5.00 mL) was added dropwise. The reaction system was kept stirring at -78°C for 1 hour. The reaction system was warmed to room temperature and saturated NH ₄ Cl (aq.) was added to quench the reaction. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic phases were washed with saturated brine (3x100 mL) and dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase flash chromatography on a C18 silica gel column under conditions of mobile phase FA-water. (2R,3R,4S,5R,6R)-3,4,5-tri(benzyloxy)-6-[(benzyloxy)methyl]-2-[4-chloro-3-(4-ethoxyphenoxy)phenyl ] Oxan-2-ol (1.2 g, yield 55.48%) was obtained as an off-white solid.

The reaction route is as follows:

(3) (2R,3R,4S,5R,6R)-3,4,5-tri(benzyloxy)-6-[(benzyloxy)methyl]-2-[4-chloro-3-(4-ethoxy) A solution of phenoxy)phenyl]oxan-2-ol (1.25 g, 1.588 mmol, 1.00 equivalents) in acetonitrile (20 mL) was placed in a flask, and the flask was evacuated and replaced with nitrogen three times. Then, the reaction system was cooled to -30°C, and after a few minutes, triethylsilane (0.69g, 4.763mmol, 3.00 equivalents) and BF ₃ -Et ₂ O (0.34g, 2.0%) were added at -30°C. 381 mmol, 1.50 eq.) was added, the reaction was stirred at -30° C. for 1 hour, and the temperature was allowed to rise to room temperature. The reaction was quenched with K ₂ CO ₃ (5 mL) and the mixture was extracted with EA (2×200 mL). The combined organic phases were concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography on a C18 silica gel column, mobile phase FA-water, detector UV 254 nm. (2R,3R,4R,5S,6R)-3,4,5-tri(benzyloxy)-2-[(benzyloxy)methyl]-6-[4-chloro-3-(4-ethoxyphenoxy)phenyl ] Oxane (1.2 g, yield 97.99%) was obtained as a colorless oil.

The reaction route is as follows:

(4) Under stirring conditions at room temperature, (2R,3R,4R,5S,6R)-3,4,5-tri(benzyloxy)-2-[(benzyloxy)methyl]-6-[4- To a solution of chloro-3-(4-ethoxyphenoxy)phenyl]oxane (500.00 mg, 0.648 mmol, 1.00 eq.) in MeOH (50 mL) was added Pd/C (150.00 mg, 1.410 mmol, 2.17 equivalent amount) was added. The mixture was stirred under a hydrogen atmosphere at room temperature and under a pressure of 5 atm overnight. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified by preparative liquid phase chromatography on an XBridge Prep OBD C18 chromatography column (19 x 250 mm, 5 um), mobile phase A water (0.05% NH ₃ H ₂ O), mobile phase B acetonitrile, flow rate 25 mL/min, It was purified under the conditions of gradient 25B to 40B, elution time 12 min, UV detector 254 nm, RT1 of 11.02. (2R,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxyphenoxy)phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol (92 mg, yield 34.03%) was obtained as an off-white solid.

The reaction route is as follows:

LC-MS 3: (ES, m/z): [M-1]=409
H-NMR 3: ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 7.42 (d, J = 8.2 Hz, 1H), 7.17 (dd, J = 8.2, 1.9 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H), 6.89 (s, 4H), 4.11 - 3.95 (m, 3H), 3.85 (d, J = 11.9 Hz, 1H), 3.71 - 3.54 (m, 1H), 3.56 - 3.34 (m, 3H) ), 3.21 (t, J = 9.0 Hz, 1H), 1.38 (t, J = 7.0 Hz, 3H).

In addition, in the present invention, the following compounds were manufactured using a similar method. The structural formulas and mass spectrometry data of those compounds are shown in the table below.

In order to evaluate the medicinal efficacy of the glycoside derivatives according to the present invention, the following examples of biological activity were studied.

Examples regarding biological activity:
Test Example 1 - In vitro SGLT2 inhibitory activity

By establishing a cell model overexpressing SGLT2, fluorescent glucose (2-[N-(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-2-deoxy-D-glucose, Using the 2-deoxy-1-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-D-glucose, 1-NBDG) tracer method, we tested compounds on SGLT2-mediated glucose uptake. We investigated the effects and discovered a candidate compound with SGLT2 inhibitory activity.

1. Materials and Methods (1) Materials A human SGLT2 overexpressing cell line (CHO-SGLT2) constructed from Chinese hamster ovary cells CHO was cultured in 1640 medium (Gibco) and 10% imported fetal bovine serum (Gibco, 10270). ), the cells were subcultured at a ratio of 1:3, and the culture medium was replaced three times a week. Fluorescence detection cell culture plates and other culture flasks were purchased from Corning. Dapagliflozin served as a positive control, and the test compounds were Compound 2 and Compound 3. Appropriate amounts of the compounds were weighed, a 100 mM stock solution was prepared in DMSO, and stored in the dark at 4°C.

(2) Main reagents Preparation of Choline buffer: 140mM choline chloride, 5mM KCl, 2.5mM CaCl ₂ , 1mMmgSO ₄ , 1mM KH ₂ PO ₄ , 10mM HEPES, pH = 7.4 with Tris base It was adjusted. It was filtered through a 0.22 μm membrane.

Preparation of sodium salt incubation solution (Na ⁺ Sodium buffer): 140mM NaCl, 5mM KCl, _2.5mM CaCl2, _1mMmgSO4 , 1mM _KH2PO4 , _10mM HEPES, adjusted to pH=7.4 with Tris base.

Preparation of neutral decomposition solution: 1% Nonidet P-40, 1% sodium deoxycholate, 40mM KCl, 20mM Tris base, pH adjusted to 7.4.

(3) Equipment Multifunctional microplate reader Biotek Synergy2

(4) Detection of NBDG uptake into cells:
Prior to 1-NBDG uptake detection, CHO-SGLT2 cells were digested and seeded at 40,000 cells/well in a 96-well cell culture plate, and after continuing to culture the cells for 48 hours, the medium was aspirated and discarded. , add 100 μl of choline buffer to each well, starve the cells for 30 min at 37°C, discard the choline buffer, and add 100 μl of freshly prepared sodium salt incubation solution containing 100 μM 1-NBDG and test compound. was added, the solvent DMSO served as a negative control for the test compound, and the sodium salt incubation solution without 1-NBDG served as a blank control. After continuing the culture for 1 hour, the incubation solution was aspirated, the cells were washed three times with choline buffer, 50 μl of neutral digestion solution was added to each well, the cells were digested on ice for 10 min, and the fluorescence value of each well was determined. Detection was performed using a multifunctional microplate reader Em = 485/20 nm, Ex = 528/20 nm.

(5) Calculation and statistical methods Experiments were repeated at least three times for a fixed concentration of each compound, and data were expressed as mean ± SEM. 1-NBDG cellular uptake amount=fluorescence value _1-NBDG -fluorescence value _Blank was calculated. SGLT2 glucose uptake inhibition rate (%) = (uptake amount _control - uptake amount _compound )/uptake amount _control x 100% was calculated. Concentration-inhibition curves were generated using Graphpad Prism software and IC ₅₀ values were calculated.

2. Results For each compound, the stock solution was diluted 10/20 times and several concentration gradients were set up according to the preliminary experimental results (see Table 1). The effects of compounds at various concentrations on cellular 1-NBDG uptake were expressed as percentage inhibition of SGLT2 by each compound at a specific concentration (Table 1). A concentration-inhibition rate curve (Figure 4) for each compound was created, and the maximum inhibitory activity of the positive control dapagliflozin (dapagliflozin) was set as 100%, and the relative maximum activity (Max%) of each compound and the IC ₅₀ of SGLT2 inhibition of the compound were calculated. The values were calculated (Table 2).

From the above results, it was found that the compound according to the present invention has good SGLT2 inhibitory activity.

Test Example 2 Evaluation of in vivo activity of the compound according to the present invention (effect on blood sugar level after oral glucose loading in normal mice)

1. Materials and Methods (1) Animals ICR mice (male, 18-20 g) purchased from Beijing Wetong Lihua Experimental Technology Co., Ltd. were adaptively housed for 4 days, and randomly divided into 8 mice in each group and a normal control group. The subjects were divided into four groups: a positive control group, and two test compound groups.

(2) Setting the compound and dose Taking Compound 2 according to the present invention as an example, animal experiments were conducted at two doses of 2 mg/kg and 4 mg/kg, and the dose of dapagliflozin, a positive control drug, was 2 mg/kg. And so. The stock solution was diluted with double distilled water to the appropriate concentration.

(3) Experimental design Mice were fasted overnight, and the normal control group was intragastrically administered with 0.5% DMSO in double-distilled water (note: the stock solution was prepared in DMSO), and the positive control group was given dapagliflozin. Compound 2 was administered intragastrically at 2 mg/kg and two test compound groups at 2 mg/kg and 4 mg/kg, respectively. One hour later, blood was collected at 0 minutes (fasting), and then a glucose (2.0 g/kg) solution was intragastrically administered to each group of mice. Blood was collected 30, 60, and 120 minutes after glucose administration, blood sugar levels were measured by the glucose oxidase-peroxidase method, and the area under the blood sugar curve was calculated.

(4) Statistical method Data were expressed as mean±SD, one-way analysis of variance was used for comparisons between multiple groups, and Dunnett's t test was used for comparisons between two groups. Statistical graphs were generated using Graphpad Prism software.

The results are shown in Tables 5 and 3.
Table 5 is a graph showing the effect of Compound 2 on the blood glucose curve and area under the blood glucose curve after oral glucose loading in normal ICR mice. ***p<0.001, vs. Nor group.

Compared to the normal control group (Nor), the positive control drug dapagliflozin not only lowered fasting blood glucose (P<0.001) but also lowered blood glucose levels at each time point after glucose loading. significantly (P<0.001) and reduced the area under the blood glucose curve (AUC) by 35.2% (P<0.001). Test compound 2 administered at two doses of 2 mg/kg and 4 mg/kg lowered fasting blood glucose (P<0.001) and significantly lowered blood glucose levels by 37.5% at each time point after glucose loading. 4% (P<0.001), and the area under the curve (AUC) was also significantly reduced to 42.9% (P<0.001), which was superior to the positive control drug dapagliflozin.

Test Example 3 In vivo study on the medicinal effects of the compound according to the present invention in anti-alloxan diabetes model mice

1. Materials and Methods (1) Animals Alloxan diabetic mice were used. Normal ICR mice (male, 22-24 g) were randomly divided into normal group, model group (con), positive control group, and four dose test compound groups (n = 11) and injected with alloxan. Mice that were not treated were used as a normal control group (n=10).

(2) Setting of test compound and dosage For Compound 2 according to the present invention, which is an example, four doses of 0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg were administered. The dose was set. The dose of dapagliflozin, a positive control drug, was 2.0 mg/kg.

(3) Experimental design The drug was administered to mice by intragastric administration. The positive control group was given dapagliflozin (2.0 mg/kg), and the test group was given different doses of compound 2 (0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg and 2.0 mg/kg). I gave it to you.

Single administration: Fasting blood (0 min) was collected after the mice were fasted for 3 hours, then the drug was intragastrically administered to each group of mice, and after 1 hour administration, glucose (2.0 mg/kg ) solution was administered intragastrically. Blood was collected 30, 60, 120, and 180 minutes after glucose administration, blood sugar levels were measured by the glucose oxidase-peroxidase method, and the area under the blood sugar curve was calculated.

On the 6th day of continuous administration, the mice were not fasted, and blood was collected before administration (0 o'clock), 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration, and blood glucose levels were measured.

On the 9th day of continuous administration, mice were fasted for 1 hour and then administered intragastrically, and after the 1 hour administration, an oral glucose tolerance test (OGTT) was conducted.

On the 16th day of continuous administration, the mice were not fasted, and urine was collected 1 hour after each administration to measure the urine sugar concentration.

On the 22nd day of continuous administration, mice were fasted for 1 hour and then administered intragastrically, and after 1 hour of administration, blood was collected and fasting blood sugar was measured.

On the 28th day of continuous administration, the mice were not fasted, and blood was collected 1 hour after each administration to measure random blood sugar levels.

On the 32nd day of continuous administration, the mice were not fasted and blood was collected to measure glycated hemoglobin (HbA1c).

(4) Statistical method Data were expressed as mean±SEM (n=10-11), one-way analysis of variance was used for comparisons between multiple groups, and Dunnett's test was used for comparisons between two groups. Statistical graphs were generated using Graphpad Prism software.

2. Results (1) Single administration of Compound 2 (0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg and 2.0 mg/kg) reduced blood glucose levels and The area under the blood sugar curve (AUC) could be significantly reduced. Under the condition of the same dosage, the strength of action was better than the positive control drug.

(2) Continuous administration of Compound 2 (0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg and 2.0 mg/kg) for 6 days reduced non-fasting blood glucose levels in alloxan diabetic mice. There was a significant decrease (p<0.001 or p<0.01) in the area under the glycemic curve (AUC) and improved oral glucose tolerance. Dapagliflozin (2.0 mg/kg) had a significantly weakened hypoglycemic effect after 8 hours, and no significant effect after 24 hours; /kg and 2.0 mg/kg) showed good hypoglycemic activity from 8 hours to 24 hours. Compound 2 (0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg and 2.0 mg/kg) had a longer duration of drug effect than the positive control drug compared to dapagliflozin (2.0 mg/kg). significantly longer than dapagliflozin (p<0.05, p<0.01 or p<0.001).

(3) Compound 2 (0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg and 2.0 mg/kg) was administered multiple times in succession, resulting in alloxan diabetes on the 9th and 22nd day. It was possible to significantly lower the fasting blood glucose level of mice (p<0.001). Compound 2 (1.0 mg/kg and 2.0 mg/kg) was able to lower blood sugar levels more significantly compared to the positive control drug dapagliflozin (2.0 mg/kg) (p<0.01 ), its potency was significantly superior to that of the positive control drug.

(4) Continuous administration of compound 2 (0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg and 2.0 mg/kg) for 28 days significantly reduced random blood sugar levels in alloxan diabetic mice. (p<0.001). Compound 2 (0.5 mg/kg, 1.0 mg/kg and 2.0 mg/kg) was able to lower blood glucose levels more significantly compared to the positive control drug dapagliflozin (2.0 mg/kg). It was possible (p<0.05, p<0.01). Continuous administration of Compound 2 (0.5 mg/kg, 1.0 mg/kg and 2.0 mg/kg) for 32 days was able to significantly reduce the level of glycated blood sugar protein in alloxan diabetic mice. Compound 2 (0.5 mg/kg, 1.0 mg/kg and 2.0 mg/kg) significantly reduced glycated hemoglobin on day 32 compared to the positive control drug dapagliflozin (2.0 mg/kg). (p<0.05), and its potency was significantly superior to that of the positive control drug.

(5) Continuous administration of compound 2 (0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg and 2.0 mg/kg) for 16 days significantly increased urine sugar concentration in alloxan diabetic mice. The efficacy of this drug was superior to that of the positive control drug.

The test results are shown in Tables 4 to 7 below.

Furthermore, by continuously administering Compound 2 according to the present invention (0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg) for 22 days, the body weight and food intake of alloxan diabetic mice decreased. , there was no significant effect on drinking water, indicating that it has good safety.

Test Example 4 Medicinal effect of the compound according to the present invention on spontaneous type 2 diabetic db/db mice

1. Materials and Methods (1) Animals Spontaneous type 2 diabetic db/db mice and their normal control mice db/m mice (male, 5-6 weeks old), db/db mice have random blood sugar levels, fasting blood sugar levels, 40 Randomly divided into 6 groups: model group (con), positive control group, and 3 dose groups of test compound (n=10) according to blood glucose lowering rate, blood triglycerides, blood total cholesterol, and body weight. It was done.

(2) Setting of compound and dose In the test, Compound 2 according to the present invention was used as an example, and three doses of 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg were set. The positive control drug was dapagliflozin at a dose of 2.0 mg/kg.

(3) Experimental design The drug was administered to mice by intragastric administration. The positive control group received dapagliflozin (2.0 mg/kg) and the three compound 2 groups received 0.5 mg/kg, 1.0 mg/kg and 2.0 mg/kg of compound 2, respectively.

The mice were fasted for 2 hours and blood was collected at 0:00 (fasting), and then intragastrically administered to each group of mice, 1, 2, 4, 6, and 8 hours after administration. After 24 hours, blood was collected, blood sugar levels were measured by the glucose oxidase-peroxidase method, and the area under the blood sugar curve was calculated. At the same time, urine was collected 2 hours and 4 hours after administration, and the urine sugar concentration was measured.

On the 15th day of continuous administration, blood was collected before the mice were fasted to measure random blood sugar levels, and 2 hours after the mice were fasted and given the compound, blood was collected to measure fasting blood sugar levels.

On the 22nd day of continuous administration, the mice were fasted and 2 hours after administration of the compound, blood was collected to measure blood sugar levels, blood triglycerides, and total cholesterol.

On the 28th day of continuous administration, blood was collected from each mouse without fasting, and random blood glucose levels and glycated hemoglobin (HbA1c) were measured.

(4) Statistical method Data were expressed as mean±SEM (n=10), one-way analysis of variance was used for comparisons between multiple groups, and Dunnett's test was used for comparisons between two groups. Statistical graphs were generated using Graphpad Prism software.

2. Results (1) Single administration of compound 2 (0.5 mg/kg, 1.0 mg/kg and 2.0 mg/kg) according to the present invention resulted in spontaneous type 2 diabetic db/db mice post-administration 1 The fasting blood glucose level was significantly lowered (p<0.001 or p<0.01) at 2 hours, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours, and below the blood sugar curve. The area (AUC) could be significantly reduced. Compound 2 (0.5 mg/kg, 1.0 mg/kg and 2.0 mg/kg) had a higher potency than the positive control drug dapagliflozin (2.0 mg/kg). <0.01 or p<0.001). A single dose of Compound 2 (0.5 mg/kg, 1.0 mg/kg and 2.0 mg/kg) lowers blood glucose levels in spontaneous type 2 diabetic db/db diabetic mice for up to 24 hours. This was significantly longer than the positive control drug dapagliflozin (2.0 mg/kg).

(2) Single administration of compound 2 according to the present invention (0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg) increased urine sugar concentration in db/db mice 2 hours after administration. However, 4 hours after administration, the urinary sugar concentration of db/db mice no longer increased. Compound 2 was found to have the same effect as the positive control drug dapagliflozin.

(3) Compound 2 according to the present invention (0.5 mg/kg, 1.0 mg/kg and 2.0 mg/kg) was administered multiple times in succession to induce spontaneous type 2 diabetic db/db mice at different doses. It was possible to significantly lower fasting blood sugar and random blood sugar levels. Under the same dosage conditions, compound 2 (2.0 mg/kg) had significantly stronger efficacy than the positive control drug dapagliflozin (2.0 mg/kg) (p<0.001, p< 0.01 or p<0.05).

(4) Spontaneous type 2 diabetic db/db diabetic mice at different doses on the 22nd day of continuous administration of compound 2 according to the present invention (0.5 mg/kg, 1.0 mg/kg and 2.0 mg/kg) could significantly reduce blood triglyceride (TG) levels and had no effect on blood cholesterol levels. It was found that there was no difference between Compound 2 according to the invention and dapagliflozin, the positive drug and positive control drug.

(5) Spontaneous type 2 diabetes db/db diabetes at different doses due to continuous administration of compound 2 according to the present invention (0.5 mg/kg, 1.0 mg/kg and 2.0 mg/kg) for 28 days It was able to significantly reduce glycated blood sugar protein levels in mice. Under the same dosage conditions, Compound 2 (2.0 mg/kg) according to the present invention was found to be more effective than the positive control drug dapagliflozin (2.0 mg/kg).

(6) Continuous administration of compound 2 according to the present invention (0.5 mg/kg, 1.0 mg/kg and 2.0 mg/kg) resulted in changes in body weight, food intake and There were no significant effects on drinking water.

The results are shown in Tables 8 to 11 below.

From the above results, Compound 2 according to the present invention has a superior blood glucose lowering duration than the positive control drug dapagliflozin in spontaneous type 2 diabetic mice, a stronger fasting blood glucose lowering effect than the positive control drug, and a random It was found to have a particularly advantageous effect of lowering blood sugar levels and having a stronger effect of lowering glycated blood sugar protein levels than the positive control drug. The above results showed that the compound according to the present invention has excellent medicinal efficacy and good safety.

Test Example 5 Safety study of the compound according to the present invention The following mouse acute toxicity study was conducted on the compound according to the present invention.

1. Purpose of the Test Using Compound 2 according to the present invention as an example, the strength of the acute toxic reaction caused by oral administration of dapagliflozin to mice was compared.

2. Dose Setting Compound 2 and dapagliflozin were intragastrically administered at a dose of 3000 mg/kg to mice, and the difference in acute toxicity between Compound 2 and dapagliflozin was compared.

3. Detection frequency and detection method of indicators 3.1 General condition observation and mortality After administration, animals were observed by the cage once a day for 7 consecutive days, especially within 4 hours after administration, to determine their toxicity. Reaction symptoms and time of death were recorded.

3.2 Test Groups Mice were randomly divided into three groups according to body weight, 10 mice in each group, half male and half female: blank control group, dapagliflozin group, and 2 compound groups. On the day before administration, the animals were fasted for 17 hours and water was not prohibited, and the corresponding test product was intragastrically administered to each test product group, and the same dose of vehicle was intragastrically administered once to the blank control group. .

4. Experimental Results When the compound 2 group and the dapagliflozin group were given a sample solution at an equal dose of 3000 mg/kg intragastrically to mice, the toxicity of the compound 2 group was significantly lower than that of the dapagliflozin group. There was also a large sex difference in animal mortality in both groups, with all males dying and no females dying.

The above description of the embodiments is only used to understand the method of the present invention and its gist. It will be appreciated by those skilled in the art that several improvements and modifications can be made to the present invention without departing from the principles of the invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention. It is necessary to keep this in mind.

Claims (17)

A glycoside derivative which is a compound represented by the following formula I or a pharmaceutically acceptable salt thereof.
(wherein A is an oxygen atom, -(CH ₂ ) _m - or -NH-, m is 1, 2 or 3,
B is an oxygen atom or a sulfur atom,
R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are independently hydrogen, hydroxy group, carboxy group, halogen, -CN, alkyl group, alkoxy group, alkoxyalkoxy group, cycloalkyl group, Aryl group, heteroaryl group, -O-aryl group, -O-heteroaryl group, -OCH ₂ -aryl group, -OCH ₂ -heteroaryl group, -O-heterocyclyl group, -OCH ₂ -heterocyclyl group, ester group , -NR ₁₁ R _11a , and a 3- to 14-membered heterocyclyl group containing 1 to 4 heteroatoms selected from N, O, S, SO and/or SO ₂ ,
Alternatively, said R ₁ and R ₂ are taken together to form a heterocyclyl group, cycloalkyl group, aryl group or heteroaryl group fused to a benzene ring, and/or said R ₃ and R ₄ are taken together , forming a cyclopentyl group or oxacyclopentyl group fused to a benzene ring,
R ₇ , R ₈ , R ₉ , R ₁₀ are independently selected from the group consisting of hydrogen, hydroxy group, alkyl group, alkoxy group and alkylthio group,
R ₁₁ and R _11a are independently selected from the group consisting of a hydrogen atom and an alkyl group,
Here, the alkyl group, alkoxy group, alkoxyalkoxy group, cycloalkyl group, aryl group, heteroaryl group, -O-aryl group, -O-heteroaryl group, -OCH ₂ -aryl group, -OCH ₂ -hetero Aryl group, -O-heterocyclyl group, -OCH ₂ -heterocyclyl group, ester group, -NR ₁₁ R _11a , heterocyclyl group, alkylthio group are halogen, hydroxy group, amino group, carboxy group, cyano group, alkyl group, alkoxy It may be further substituted with one or more substituents selected from the group consisting of nitro groups and nitro groups. ) R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are independently hydrogen, hydroxy group, carboxy group, halogen, -CN, C1-C6 alkyl group, C1-C6 alkoxy group, C2 ~C16 alkoxyalkoxy group, C3-C6 cycloalkyl group, C6-C12 aryl group, C2-C12 heteroaryl group, -O-C6-C12 aryl group, -O-C2-C12 heteroaryl group, -OCH ₂ -C6 ~C12 aryl group, -OCH ₂ -C2 to C12 heteroaryl group, -O-C2 to C6 heterocyclyl group, -OCH ₂ -C2 to C6 heterocyclyl group, C1 to C6 ester group, -NR ₁₁ R _11a , and N, selected from the group consisting of 3- to 14-membered heterocyclyl groups containing 1 to 4 heteroatoms selected from O, S, SO and/or _SO2 ,
Alternatively, said R ₁ and R ₂ together contain 3 to 4 heteroatoms selected from N, O, S, SO and/or SO ₂ fused to a benzene ring. forming a member heterocyclyl group, C3-C6 cycloalkyl group, C6-C12 aryl group, or C2-C12 heteroaryl group,
R ₇ , R ₈ , R ₉ , and R ₁₀ are independently selected from the group consisting of hydrogen, hydroxy group, C1-C6 alkyl group, C1-C6 alkoxy group, and C1-C6 alkylthio group,
The glycoside derivative according to claim 1, wherein R ₁₁ and R _11a are independently selected from the group consisting of a hydrogen atom and a C1 to C6 alkyl group. The A is an oxygen atom or -CH ₂ -,
Said B is an oxygen atom,
R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are independently hydrogen, hydroxy group, carboxy group, fluorine, chlorine, bromine, -CN, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, isopentyl group, n-hexyl group, isohexyl group, methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, n-butyloxy group, isobutyloxy group, t-butyloxy group, n-pentyloxy group, isopentyloxy group, n-hexyloxy group, methoxymethoxy group, ethoxymethoxy group, ethoxyethoxy group, n-propoxymethoxy group, iso Propoxymethoxy group, n-propoxyethoxy group, isopropoxyethoxy group, cyclopropyl group, methylcyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, phenyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyrrolyl group, thienyl group , furanyl group, oxazolyl group, thiazolyl group, imidazolyl group, triazolyl group, phenoxy group, pyridyloxy group, pyrimidinyloxy group, pyrrolyloxy group, furanyloxy group, thienyloxy group, oxazolyloxy group, benzyloxy group, -OCH ₂ -pyridyl group, -OCH ₂ -pyrimidinyl group, -OCH ₂ -pyrrolyl group, -OCH ₂ -thienyl group, -OCH ₂ -furanyl group, -OCH ₂ -oxazolyl group, -OCH ₂ -thiazolyl group, -OCH ₂ - Imidazolyl group, -OCH ₂ -triazolyl group, methyl ester group, ethyl ester group, isopropyl ester group, sulfonic acid ester group, amino group, hexahydropyridyl group, hexahydropyrazinyl group, morpholinyl group, tetrahydropyrrolyl group and tetrahydroxazolyl groups (one or more hydrogen atoms of these groups may be halogen, hydroxy group, amino group, carboxy group, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, and nitro The glycoside derivative according to claim 1 or 2, which is further substituted with one or more substituents selected from the group consisting of groups. The R ₁ and R ₂ are a cyclohexyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyrrolyl group, a thienyl group, a furanyl group, an oxazolyl group, a thiazolyl group, or an imidazolyl group, which are fused together to a benzene ring. , a triazolyl group, a hexahydropyridyl group, a hexahydropyrazinyl group, a morpholinyl group, a tetrahydropyrrolyl group, a tetrahydroxazolyl group, or a dioxane. The glycoside derivatives described in . R ₇ , R ₈ , R ₉ , and R ₁₀ are independently hydrogen, hydroxy group, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, isopentyl group, n-hexyl group, isohexyl group, hydroxymethyl group, hydroxyethyl group, methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, n-butyloxy group, isobutyloxy group, t -butyloxy group, n-pentyloxy group, isopentyloxy group, n-hexyloxy group, methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, isobutylthio group, t-butylthio group, The glycoside derivative according to any one of claims 1 to 4, which is selected from the group consisting of n-pentylthio group, isopentylthio group, or n-hexylthio group. The glycoside derivative according to any one of claims 1 to 5, which is a compound represented by the following formula II or a pharmaceutically acceptable salt thereof.
(wherein A is an oxygen atom, -(CH ₂ ) _m - or -NH-, m is 1, 2 or 3,
B is an oxygen atom or a sulfur atom,
R ₃ , R ₄ , R ₅ , and R ₆ are independently hydrogen, hydroxy group, carboxy group, halogen, -CN, alkyl group, alkoxy group, alkoxyalkoxy group, cycloalkyl group, aryl group, heteroaryl group, -O-aryl group, -O-heteroaryl group, -OCH ₂ -aryl group, -OCH ₂ -heteroaryl group, -O-heterocyclyl group, -OCH ₂ -heterocyclyl group, ester group, -NR ₁₁ R _11a , and a 3- to 14-membered heterocyclyl group containing 1 to 4 heteroatoms selected from N, O, S, SO and/or _SO2 ,
_R10 is selected from the group consisting of hydrogen, hydroxy group, alkyl group, alkoxy group and alkylthio group,
R ₁₁ and R _11a are independently selected from the group consisting of a hydrogen atom and an alkyl group,
Here, the alkyl group, alkoxy group, alkoxyalkoxy group, cycloalkyl group, aryl group, heteroaryl group, -O-aryl group, -O-heteroaryl group, -OCH ₂ -aryl group, -OCH ₂ -hetero Aryl group, -O-heterocyclyl group, -OCH ₂ -heterocyclyl group, ester group, -NR ₁₁ R _11a , heterocyclyl group, alkylthio group are halogen, hydroxy group, amino group, carboxy group, cyano group, alkyl group, alkoxy It may be further substituted with one or more substituents selected from the group consisting of nitro groups and nitro groups. ) R ₃ , R ₄ , R ₅ , and R ₆ are independently hydrogen, hydroxy group, carboxy group, fluorine, chlorine, bromine, -CN, C1 to C6 alkyl group, C1 to C6 alkoxy group, C2 to C16 selected from the group consisting of alkoxyalkoxy groups,
The glycoside derivative according to claim 6, wherein R ₁₀ is selected from the group consisting of hydrogen, hydroxy group, C1-C6 alkyl group, C1-C6 alkoxy group, and C1-C6 alkylthio group. The R ₃ is selected from the group consisting of a C1-C3 alkyl group and a C1-C3 alkoxy group,
The R ₄ , R ₅ and R ₆ are hydrogen,
R ₁₀ is selected from the group consisting of hydrogen, hydroxy group, C1-C3 alkyl group, C1-C3 alkoxy group, and C1-C3 alkylthio group,
The C1-C3 alkyl group, C1-C3 alkoxy group, or C1-C3 alkylthio group has one or more substituents selected from the group consisting of halogen, hydroxy group, amino group, carboxy group, cyano group, and nitro group. The glycoside derivative according to claim 6 or 7, which may be further substituted by. A is an oxygen atom or -(CH ₂ )-,
B is an oxygen atom,
R ₁ and R ₂ together form a 5- to 6-membered heterocyclyl group fused to a benzene ring, or a cyclobutanyl group fused to a benzene ring, and the 5- to 6-membered heterocyclyl group is a 5- to 6-membered heterocyclyl group containing 1 or 2 heteroatoms selected from O and S,
R ₃ is selected from the group consisting of CH ₃ (CH ₂ ) _n -, CH ₃ (CH ₂ ) _n O- and halogen, n is selected from 0, 1, 2 and 3;
R ₄ is hydrogen;
Alternatively, R ₃ and R ₄ together form a cyclopentyl group or an oxacyclopentyl group fused to a benzene ring,
R ₅ and R ₆ are hydrogen;
R ₇ , R ₈ and R ₉ are hydroxy groups,
The glycoside derivative according to any one of claims 1 to 7, wherein R ₁₀ is selected from the group consisting of a hydroxyalkyl group, an alkoxy group, and an alkylthio group. A is an oxygen atom or -(CH ₂ )-,
B is an oxygen atom,
R ₁ and R ₂ together form a 5- to 6-membered heterocyclyl group fused to a benzene ring, or a cyclobutanyl group fused to a benzene ring, and the 5- to 6-membered heterocyclyl group is A 5- to 6-membered heterocyclyl group containing 1 or 2 oxygen atoms,
R ₃ is selected from the group consisting of CH ₃ (CH ₂ ) _n -, CH ₃ (CH ₂ ) _n O- and halogen, n is selected from 0, 1, 2 and 3;
R ₄ is hydrogen;
Alternatively, R ₃ and R ₄ together form a cyclopentyl group or an oxacyclopentyl group fused to a benzene ring,
R ₅ and R ₆ are hydrogen;
R ₇ , R ₈ and R ₉ are hydroxy groups,
The glycoside derivative according to claim 9, wherein _R10 is selected from the group consisting of a hydroxymethyl group, a methoxy group, and a methylthio group. A is an oxygen atom,
B is an oxygen atom,
R ₁ is selected from the group consisting of C1-C3 alkoxy groups,
R ₂ is hydrogen;
R ₃ is selected from halogen, preferably fluorine, chlorine or bromine;
R ₄ is hydrogen;
R ₅ and R ₆ are hydrogen;
R ₇ , R ₈ and R ₉ are hydroxy groups,
Glycosidic derivative according to any one of claims 1 to 7, wherein R ₁₀ is selected from hydroxyalkyl groups, preferably hydroxymethyl groups. The glycoside derivative according to any one of claims 1 to 11, having any of the following structures:
The glycoside derivative according to any one of claims 1 to 12, which comprises producing a compound represented by the following formula Ia from a compound represented by the following formula III through a deprotection reaction. manufacturing method.
(wherein A is an oxygen atom, -(CH ₂ ) _m - or -NH-, m is 1, 2 or 3,
B is an oxygen atom or a sulfur atom,
R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ are independently hydrogen, hydroxy group, carboxy group, halogen, -CN, alkyl group, alkoxy group, alkoxyalkoxy group, cycloalkyl group, aryl group, heteroaryl group, -O-aryl group, -O-heteroaryl group, -OCH ₂ -aryl group, -OCH ₂ -heteroaryl group, -O-heterocyclyl group, -OCH ₂ -heterocyclyl group, ester group, -NR ₁₁ R _11a and a 3- to 14-membered heterocyclyl group containing 1 to 4 heteroatoms selected from N, O, S, SO and/or SO ₂ ,
Alternatively, R ₁ and R ₂ together form a heterocyclyl group, cycloalkyl group, aryl group or heteroaryl group fused to a benzene ring,
R ₁₀ is a hydroxymethyl group,
R ₁₁ and R _11a are independently selected from the group consisting of a hydrogen atom and an alkyl group,
Here, the alkyl group, alkoxy group, alkoxyalkoxy group, cycloalkyl group, aryl group, heteroaryl group, -O-aryl group, -O-heteroaryl group, -OCH ₂ -aryl group, -OCH ₂ -hetero Aryl group, -O-heterocyclyl group, -OCH ₂ -heterocyclyl group, ester group, -NR ₁₁ R _11a , heterocyclyl group, alkylthio group are halogen, hydroxy group, amino group, carboxy group, cyano group, alkyl group, alkoxy may be further substituted with one or more substituents selected from the group consisting of groups and nitro groups,
R ₁₂ is an alkyl group, trimethylsilyl group, benzyl group, formyl group, acetyl group, tetrahydropyranyl group, methoxymethyl group or t-butyldimethylsilyl group. ) The process according to any one of claims 1 to 12, comprising producing a compound represented by the following formula I-a from a compound represented by the following formula VII through a sulfurization reaction and a deprotection reaction. Method for producing glycoside derivatives.
(wherein A is an oxygen atom, -(CH ₂ ) _m - or -NH-, m is 1, 2 or 3,
B is an oxygen atom or a sulfur atom,
R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ are independently hydrogen, hydroxy group, carboxy group, halogen, -CN, alkyl group, alkoxy group, alkoxyalkoxy group, cycloalkyl group, aryl group, heteroaryl group, -O-aryl group, -O-heteroaryl group, -OCH ₂ -aryl group, -OCH ₂ -heteroaryl group, -O-heterocyclyl group, -OCH ₂ -heterocyclyl group, ester group, -NR ₁₁ R _11a and a 3- to 14-membered heterocyclyl group containing 1 to 4 heteroatoms selected from N, O, S, SO and/or SO ₂ ,
Alternatively, R ₁ and R ₂ together form a heterocyclyl group, cycloalkyl group, aryl group or heteroaryl group fused to a benzene ring,
R ₁₀ is a methylthio group,
R ₁₁ and R _11a are independently selected from the group consisting of a hydrogen atom and an alkyl group,
Here, the alkyl group, alkoxy group, alkoxyalkoxy group, cycloalkyl group, aryl group, heteroaryl group, -O-aryl group, -O-heteroaryl group, -OCH ₂ -aryl group, -OCH ₂ -hetero Aryl group, -O-heterocyclyl group, -OCH ₂ -heterocyclyl group, ester group, -NR ₁₁ R _11a , heterocyclyl group, alkylthio group are halogen, hydroxy group, amino group, carboxy group, cyano group, alkyl group, alkoxy may be further substituted with one or more substituents selected from the group consisting of groups and nitro groups,
R ₁₂ is an alkyl group, trimethylsilyl group, benzyl group, formyl group, acetyl group, tetrahydropyranyl group, methoxymethyl group or t-butyldimethylsilyl group. ) The glycoside derivative according to any one of claims 1 to 12 or the glycoside derivative produced by the production method according to claim 13 or 14, and a pharmaceutically acceptable carrier, excipient, and diluent. , an adjuvant, a vehicle or a combination thereof. The glycoside derivative according to any one of claims 1 to 12 or produced by the manufacturing method according to claim 13 or 14 in the production of a pharmaceutical for preventing, treating or alleviating diabetes and its complications. Use of a glycoside derivative or a pharmaceutical composition according to claim 15. 17. Use according to claim 16, characterized in that the diabetes is type II diabetes or type I diabetes and the complication is a cardiovascular disease due to type II or type I diabetes.